Constitutive activation of the EGFR-Ras and PI-3 kinase (PI3K) signaling pathways is a common feature in human GBM and is sufficient to cause glioblastoma-like phenotypes in mouse models. How these signaling pathways specifically control glial pathogenesis is unclear. A novel Drosophila model was created to understand the molecular basis of EGFR and PI3K driven GBM. When targeted to glia and glial precursors using genetic techniques, co-activation of EGFR and RISK in Drosophila gives rise to neoplastic, invasive glial cells that create transplantable tumor-like growths, mimicking the human disease. Genetic analyses demonstrate that EGFR and PI3K induce Drosophila glial neoplasia, in part, via a combinatorial genetic network that includes genes and pathways also commonly mutated or activated in human GBM. This model has been used to identify new regulators of glial neoplasia through genetic screens and phenotypic analyses. The genes identified in these screens represent excellent candidates for genes directly involved in the pathogenesis of human GBM. Therefore, expression and function of mammalian orthologs of Drosophila modifiers will be examined in human tumors, genetically defined mouse GBMs, and GBM cell lines. During the mentored years, one already identified Drosophila modifier gene and its mammalian ortholog will be subject to detailed analysis in both Drosophila and mammalian systems. These studies will be performed in the laboratories of my mentor, Dr. John Thomas, an expert Drosophila neurobiologist, my collaborator Dr. Inder Verma, an expert mouse geneticist and cancer biologist, and my co-mentors Drs. Webster Cavenee and Frank Furnari, both experts in GBM biology. This will provide me with the training necessary to obtain an independent faculty position at a research intensive medical school, where I will expand these studies to include another 2-3 genes. PUBLIC HEALTH RELEVANCE: These studies are expected to provide key insights into glioma pathogenesis, including the identity of genes involved in tumor cell migration and invasiveness. The products of these genes may represent excellent targets for therapeutics.